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    2-Phenyl substituted Benzimidazole derivatives: Design, synthesis, and evaluation of their antiproliferative and antimicrobial activities
    (Springer Birkhauser, 2022) Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya; Alagoz, Mehmet Abdullah; Dogen, Aylin; Burmaoglu, Serdar; Algul, Oztekin
    The inability to meet the desired outcomes of anticancer treatment and decrease in treatment success of bacterial and fungal infections accelerated research in these areas. Our research group has conducted numerous studies, especially on benzimidazole ring systems' antiproliferative and antimicrobial activities. In this study, the antiproliferative activity of benzimidazole compounds was tested against A549, A498, HeLa, A375, and HepG2 cancer cell lines by MTT assay. All compounds exhibited good to potent antiproliferative activity against all tested cancer cell lines. Compounds 6-chloro-2-(4-fluorobenzyl)-1H-benzo[d] imidazole (30) and 6-chloro-2-phenethyl-1H-benzo[d]imidazole (46) were especially active against HeLa and A375 cancer cell lines with IC50 values in the range of 0.02-0.04 mu M. In contrast, compounds 6-chloro-2-((p-tolyloxy)methyl)-1H-benzo[d] imidazole (67) and 5(6)-chloro-2-((4-hydroxyphenoxy)methyl)-1H-benzimidazole (68) were active against A549 and A498 cancer cell lines with an IC50 value of 0.08 mu M. These compounds (30, 46, 67, and 68) were less toxic to normal human cells than the positive control compound methotrexate, which was screened to determine its toxicity against normal cell lines (HEK293). In the second part of the study, all compounds were tested to demonstrate their antimicrobial properties. All compounds exhibited moderate activity against all tested bacteria and fungi. However, some phenoxy methyl derivatives 5-chloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazole (69) and 5,6-dichloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d] imidazole and (74) were most active against Candida (<3.90 mu g/mL). Molecular docking studies were carried out against certain proteins in order to identify potential targets of the antiproliferative effects of the synthesized compounds. The docking scores of the compounds were found to be significantly compatible with the antiproliferative activity results. [GRAPHICS] .
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    Structure-based inhibition of acetylcholinesterase and butyrylcholinesterase with 2-Aryl-6-carboxamide benzoxazole derivatives: synthesis, enzymatic assay, and in silico studies
    (Springer, 2024) Kuzu, Burak; Alagoz, M. Abdullah; Demir, Yeliz; Gulcin, Ilhami; Burmaoglu, Serdar; Algul, Oztekin
    An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 & Aring;) and BChE (average RMSD: 2.2 & Aring;) (donepezil had average RMSD: 1.65 & Aring; and 2.7 & Aring;, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents. [GRAPHICS] .
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    Synthesis, Biological Evaluation and In Silico Studies of Some 2-Substituted Benzoxazole Derivatives as Potential Anticancer Agents to Breast Cancer
    (Wiley-V C H Verlag Gmbh, 2022) Kuzu, Burak; Hepokur, Ceylan; Alagoz, Mehmet Abdullah; Burmaoglu, Serdar; Algul, Oztekin
    In an attempt to develop potent and selective anticancer agents, some 5- or 6- and N-substituted benzoxazol-2-carboxamide derivatives were designed, synthesized, and evaluated for their cyclooxygenase inhibitory, antioxidant, and anti-proliferative activity against MCF-7 and MDA-MB-231 cell lines. Among them 5-OMe, N-piperidine substituted (compound 30), 5-OMe, N-4-methylpiperidine substituted (compound 31) and 5-Cl, N-piperidine substituted (compound 34) benzoxazole 2-carboxamide compounds have a moderate inhibitory effect in COX-1 and COX-2 enzymes. Anti-proliferative studies show that compound 30 (IC50=5.35 mu M) and compound 31 (IC50=5.82 mu M) have similar activity to reference drug 5-FU (IC50=3.95 mu M) on MCF-7 cell but they have lower toxic effect for healthy WI-38 cell line. For the MCF-7 cell line, compounds 30 and 31 show approximately 1.5 times higher selectivity compared to the 5-FU control. Among the synthesized compounds 30, 31, and 34 had the best anti-proliferative effect and were used to perform flow cytometry and cell cycle analysis on MCF-7 cell line. To predict the binding modes and pharmacokinetic parameters of all compounds, in silico studies were carried out. These compounds may shed light on cancer treatment and cancer research.